The STAT3 inhibitor galiellalactone inhibits the generation of MDSC-like monocytes by prostate cancer cells and decreases immunosuppressive and tumorigenic factors.
Carcinogenesis
/ drug effects
Carcinogens
/ antagonists & inhibitors
Coculture Techniques
Cytokines
/ antagonists & inhibitors
Humans
Immunosuppressive Agents
/ antagonists & inhibitors
Lactones
/ pharmacology
Male
Monocytes
/ drug effects
Myeloid-Derived Suppressor Cells
/ drug effects
Prostatic Neoplasms
/ metabolism
STAT3 Transcription Factor
/ antagonists & inhibitors
Tumor Cells, Cultured
STAT3 inhibitor
cancer therapy
castration-resistant prostate cancer
myeloid-derived suppressor cells
signal transducer and activator of transcription 3
Journal
The Prostate
ISSN: 1097-0045
Titre abrégé: Prostate
Pays: United States
ID NLM: 8101368
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
08
02
2019
accepted:
02
07
2019
pubmed:
28
7
2019
medline:
19
2
2020
entrez:
27
7
2019
Statut:
ppublish
Résumé
The transcription factor signal transducer and activator of transcription 3 (STAT3) is implicated in cancer drug resistance, metastasis, and immunosuppression and has been identified as a promising therapeutic target for new anticancer drugs. Myeloid-derived suppressor cells (MDSCs) play a major role in the suppression of antitumor immunity and STAT3 is involved in the accumulation, generation, and function of MDSCs. Thus, targeting STAT3 holds the potential of reversing immunosuppression in cancer. This study aims to investigate the effect of the small molecule STAT3 inhibitor galiellalactone on prostate cancer cell- induced generation of MDSCs from monocytes and the effect on immunosuppressive factors and inflammatory cytokines. Primary human monocytes were cocultured with prostate cancer cells (DU145, PC3, and LNCaP-IL6) or with conditioned medium (CM) from prostate cancer cells in the presence or absence of the STAT3 inhibitor galiellalactone. Monocytes were analyzed by flow cytometry for an MDSC-like phenotype (CD14 Galiellalactone blocked the prostate cancer cell-induced generation of MDSC-like monocytes with an immunosuppressive phenotype ex vivo. Monocytes cultured with CM from prostate cancer cells showed increased expression of phosphorylated STAT3. Prostate cancer cells increased the expression of interleukin1β (IL1β), IL10, and IL6 in monocytes which was inhibited by galiellalactone. In addition, galiellalactone decreased indoleamine 2,3-dioxygenase gene expression in monocytes. Galiellalactone reduced the levels of IL8 and granulocyte macrophage-colony stimulating factor in prostate cancer cells per se. The STAT3 inhibitor galiellalactone may prevent the prostate cancer cell-induced generation of MDSCs and reverse the immunosuppressive mechanisms caused by the interplay between prostate cancer cells and MDSCs. This is a potential new immunotherapeutic approach for the treatment of prostate cancer.
Sections du résumé
BACKGROUND
The transcription factor signal transducer and activator of transcription 3 (STAT3) is implicated in cancer drug resistance, metastasis, and immunosuppression and has been identified as a promising therapeutic target for new anticancer drugs. Myeloid-derived suppressor cells (MDSCs) play a major role in the suppression of antitumor immunity and STAT3 is involved in the accumulation, generation, and function of MDSCs. Thus, targeting STAT3 holds the potential of reversing immunosuppression in cancer. This study aims to investigate the effect of the small molecule STAT3 inhibitor galiellalactone on prostate cancer cell- induced generation of MDSCs from monocytes and the effect on immunosuppressive factors and inflammatory cytokines.
METHODS
Primary human monocytes were cocultured with prostate cancer cells (DU145, PC3, and LNCaP-IL6) or with conditioned medium (CM) from prostate cancer cells in the presence or absence of the STAT3 inhibitor galiellalactone. Monocytes were analyzed by flow cytometry for an MDSC-like phenotype (CD14
RESULTS
Galiellalactone blocked the prostate cancer cell-induced generation of MDSC-like monocytes with an immunosuppressive phenotype ex vivo. Monocytes cultured with CM from prostate cancer cells showed increased expression of phosphorylated STAT3. Prostate cancer cells increased the expression of interleukin1β (IL1β), IL10, and IL6 in monocytes which was inhibited by galiellalactone. In addition, galiellalactone decreased indoleamine 2,3-dioxygenase gene expression in monocytes. Galiellalactone reduced the levels of IL8 and granulocyte macrophage-colony stimulating factor in prostate cancer cells per se.
CONCLUSION
The STAT3 inhibitor galiellalactone may prevent the prostate cancer cell-induced generation of MDSCs and reverse the immunosuppressive mechanisms caused by the interplay between prostate cancer cells and MDSCs. This is a potential new immunotherapeutic approach for the treatment of prostate cancer.
Identifiants
pubmed: 31348843
doi: 10.1002/pros.23885
pmc: PMC6771992
doi:
Substances chimiques
Carcinogens
0
Cytokines
0
Immunosuppressive Agents
0
Lactones
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
galiellalactone
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1611-1621Informations de copyright
© 2019 The Authors. The Prostate Published by Wiley Periodicals, Inc.
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